Senescence-Associated Metabolomic Phenotype in Primary and iPSC-Derived Mesenchymal Stromal Cells.

Eduardo Fernandez-Rebollo,Torsten Sieben,Alina Ostrowska,Jonathan Hollmann,Julia Franzen,Matteo Oliverio,Wolfgang Wagner,Björn Rath,Jan-Wilhelm Kornfeld,Roman Goetzke

doi:10.1016/j.stemcr.2019.12.012

Eduardo Fernandez-Rebollo, Torsten Sieben + Show 8 more

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https://doi.org/10.1016/j.stemcr.2019.12.012

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SummaryLong-term culture of primary cells is characterized by functional and secretory changes, which ultimately result in replicative senescence. It is largely unclear how the metabolome of cells changes during replicative senescence and if such changes are consistent across different cell types. We have directly compared culture expansion of primary mesenchymal stromal cells (MSCs) and induced pluripotent stem cell-derived MSCs (iMSCs) until they reached growth arrest. Both cell types acquired similar changes in morphology, in vitro differentiation potential, senescence-associated β-galactosidase, and DNA methylation. Furthermore, MSCs and iMSCs revealed overlapping gene expression changes, particularly in functional categories related to metabolic processes. We subsequently compared the metabolomes of MSCs and iMSCs and observed overlapping senescence-associated changes in both cell types, including downregulation of nicotinamide ribonucleotide and upregulation of orotic acid. Taken together, replicative senescence is associated with a highly reproducible senescence-associated metabolomics phenotype, which may be used to monitor the state of cellular aging.

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In vitro culture of primary cells is associated with continuous changes that result in replicative senescence: the proliferation rate declines, cells enlarge, and they lose differentiation potential (Campisi and d’Adda di Fagagna, 2007)
Syngeneic mesenchymal stromal cells (MSCs) and induced pluripotent stem cell-derived MSCs (iMSCs) were subsequently expanded until the cells entered proliferation arrest
The changes in cellular morphology were very comparable between MSCs and iMSCs: at early passages they displayed spindle-shaped fibroblast-like morphology, whereas cells at later passages were enlarged, with flattened ‘‘fried egg’’ morphology (Figure 1B)

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Introduction

In vitro culture of primary cells is associated with continuous changes that result in replicative senescence: the proliferation rate declines, cells enlarge, and they lose differentiation potential (Campisi and d’Adda di Fagagna, 2007). These profound changes in the course of culture expansion hamper the reproducibility of experiments, which is of particular relevance in regenerative medicine (Wagner and Ho, 2007). Mesenchymal stromal cells (MSCs) acquire continuous changes in gene expression and DNA methylation over subsequent passages, which can be used to track the state of cellular aging (Koch et al, 2012; Li et al, 2017; Schellenberg et al, 2014; Wagner et al, 2008). Little is known about the metabolomic changes that may be associated with or even contribute to the process of cellular aging

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